Review article

The genetics of sports injuries and athletic performance

Nicola Maffulli1 Katia Margiotti2 Umile Giuseppe Longo3 Mattia Loppini3 Vito Michele Fazio2 Vincenzo Denaro3

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Centre for Sports and Exercise Medicine, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Mile End Hospital, London, UK Department of Physical and Rehabilitation Medicine, University of Salerno, Italy Department of Surgical Pathology, Campus BioMedico University, Trigoria, Rome, Italy Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University, Trigoria, Rome, Italy

muscle performance. The most studied include ACE and ACTN3 genes. Conclusions: genetics determines the response of an individual to the surrounding environment. Recently, some of the individual genetic variations contributing to the athletic performance and the onset of musculoskeletal injuries, particularly in tendon and ligament tissues, have been identified. However, the identification of the genetic background related to susceptibility to injuries and physical performance of the athletes is challenging yet and further studies must be performed to establish the specific role of each gene and the potential effect of the interaction of these. KEY WORDS: sports injuries, athletic performance, genetics, single nucleotide polymorphisms.

Introduction Corresponding author: Nicola Maffulli Centre for Sports and Exercise Medicine, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Mile End Hospital, London, UK Department of Physical and Rehabilitation Medicine, University of Salerno, Italy E-mail: [email protected]

Summary Purpose: in the last two decades, several evidences have been provided to support the relationship between single nucleotide polymorphisms and the susceptibility to develop injuries participating in sport and performance related to sports activity. We report up-to-date review of the genetics factors involved in tendon injuries and athletic performance. Methods: we searched PubMed using the terms “sports injuries”, “athletic performance” and “genetics” over the period 1990 to the present day. We also included non-English journals. Results: most of the currently established or putative tendinopathy susceptibility loci have been analyzed by candidate gene studies. The genes currently associated with tendon injuries include gene encoding for collagen, matrix metallopeptidase, tenascin and growth factors. Several genes have been related to the physical performance phenotypes affecting endurance capacity and Muscles, Ligaments and Tendons Journal 2013; 3 (3): 173-189

Tendinopathies account for a substantial proportion of overuse injuries associated with sports1, and are a common cause of disability2-4. Most major tendons, such as the Achilles, patellar, rotator cuff and forearm extensor tendons (amongst others) are vulnerable to overuse, which induces pathological changes in the tendon5. The term tendinopathy as a generic descriptor of the clinical conditions (both pain and pathology) associated with overuse in and around tendons6. The histological descriptive term ‘tendinosis’ (a degenerative pathology with a lack of inflammatory change) and ‘tendonitis’ or ‘tendinitis’ (implying an inflammatory process) should only be used after histopathological confirmation6. However, it should be kept in mind that, despite the use of the term ‘tendinosis’, at histopathological examination the essence of a tendinopathic lesion is a failed healing response, with haphazard proliferation of tenocytes, intracellular abnormalities in tenocytes, disruption of collagen fibres, and subsequent increase in non-collagenous matrix 7-9. Tendinopathic tendons have an increased rate of matrix remodelling, leading to a mechanically less stable tendon which is probably more susceptible to damage10. Histological studies of surgical specimens in patients with established tendinopathy consistently show either absent or minimal inflammation11-13. They generally also show hypercellularity, a loss of the tightly bundled collagen fiber appearance, an increase in proteoglycan content and, commonly, neovascularisation14,15. Inflammation seems to play a role only in the initiation, but not propagation and progression, of the disease process 16.

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Competing theories have been proposed to explain the pathogenesis of tendon pathology at specific stages and presentations of the condition17-20. A continuum of tendon pathology from asymptomatic tendons to tendon tears has been proposed21,22. Failed healing and tendinopathic features have been associated with chronic overload, but the same histopathologic characteristics also has been described when a tendon is unloaded: stress shielding seems to exert a deleterious effect 11. Unloading a tendon induces cell and matrix changes similar to those seen in an overloaded state, and decreases the mechanical integrity of the tendon21,22. Genetics is the science of heredity and variation in living organisms. It investigates gene function, genome structure, chromatin organisation, recombination rate, mutation processes, and evolutionary history, to provide a coherent understanding of the human genome and its complex relationship with human biology, physiology and disease. In the last two decades, several evidences have been provided to support the relationship between single nucleotide polymorphisms and the susceptibility to develop injuries participating in sport and performance related to sports activity23. In this current concepts review, we report up-to-date review of the genetics factors involved in tendon injuries and athletic performance.

Candidate genes associated to tendon injuries Most of the currently established or putative tendinopathy susceptibility loci were analyzed by candidate gene studies. Indentify genetic susceptibility loci to injury could lead to customize exercise recommendations for specific patient populations. Prevention strategies like avoidance of weight-bearing and high-impact sports for individuals who have risk profile genotypes would take advantage of this information.

COL1A1 (Collagen type I alpha 1 gene) Collagen type I fibrils are a major constituent of bone matrix and form strong parallel bundles of fibers in tendons and ligaments. The major two genes that regulate collagen production are the collagen Iα1 (COLIA1) and the collagen Iα2 (COLIA2) gene. The COLIA1 and COLIA2 encode collagen Iα1 and collagen Iα2 polypeptides, respectively, which associate in a 2:1 ratio to form collagen type I24. The COL1A1 gene (located on chromosome 17q21.33) contains a polymorphism in the region of intron 1 (rs1800012), a predicted binding site for the transcription factor Sp125. Some studies have shown that the functional Sp1-binding site polymorphism is associated with various complex disorders including osteoporotic fractures25, osteoarthritis26, myocardial infarction27, lumbar disc disease28 and stress urinary incontinence29. It was proposed that the G to T substitution within the intronic Sp1-binding site increases the affinity for the

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transcription factor Sp1, resulting in increased COL1A1 gene expression and the production of a weaker type I collagen homotrimer consisting of three Iα1chains instead of the conventional heterotrimers (two Iα1and one Iα2 chains)25,30. Recently, this polymorphism, has been associated with cruciate ligament ruptures31, shoulder dislocation31, anterior cruciate ligament ruptures32 in two different populations study. Khoschnau et al.31 reported that the COLIA1 Sp1 TT genotype was associated with a substantially reduced risk of cruciate ligament ruptures and shoulder dislocation ruptures, they found a substantial 85% reduced risk (95% CI 34% to 97%) of injury for those with the rare TT genotype compared with those with GG genotype. Individuals with the rare genotype TT showed a 4% prevalence in the 325 Swedish controls analyzed whereas in the 358 injured patients was underrepresented showing only 1 case in the cruciate ligament ruptures group (0.4%; n=233) and 1 case in the shoulder dislocation ruptures group (0.8%; n=126). Posthumus et al.32 reported a similar data, showing that the relative genotype frequencies of the COL1A1 Sp1 binding site polymorphism within the asymptomatic 130 white South African controls was of the 4.6% for the TT genotype while none of the 117 Caucasian patients with surgically diagnosed anterior cruciate ligament ruptures showed a TT genotype. In fact the TT genotype was significantly underrepresented in the anterior cruciate ligament ruptures group compared with the control group (P=0.031; OR=0.08; 95% CI 0.01 to 1.46). Finally, Posthumus et al.33 had shown no significant association in the allelic or genotype frequencies of the Sp1 binding site polymorphism in 126 patients with Achilles tendinopathy and 126 healthy Caucasian controls. These results suggested that the COL1A1 polymorphism potentially protects from cruciate ligament, shoulder dislocation, and anterior cruciate ligament ruptures31,32. A recent short communication reported the combined effect, from the above three published studies, of the rare TT genotype of the COL1A1 Sp1 binding site polymorphism on the risk of acute soft tissue ruptures (cruciate ligament, shoulder dislocation and Achilles tendon ruptures)34. A Fisher’s exact test was used to analyse any differences in the genotype frequencies (TT vs GT and GG) of the 581 combined control and injured groups in the three published studies. The injured groups were analysed as: 1) 350 cruciate ligament ruptures31,32; 2) 476 cruciate ligament ruptures and shoulder dislocation31,32 and 3) all 517 soft tissue ruptures (cruciate ligament, shoulder dislocation and Achilles tendon) 31-33. The rare TT genotype was significantly underrepresented in the cruciate ligament group (0.3% TT genotype; n=1) when compared with the control group (4.1% TT genotype; n=24) of all three published studies (OR=15.1; 95% CI 2.0 to 111.7; P